POS0604 ACTIVATION OF TYPE I INTERFERON PATHWAY IN SERA OF PATIENTS WITH ANTI-MELANOMA DIFFERENTIATION-ASSOCIATED GENE 5 ANTIBODY-POSITIVE DERMATOMYOSITIS
Authors: S. Nakamura, Y. Katsumata, Y. Okamoto, M. Harigai
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> We have previously reported that anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are more frequently associated with rapidly progressive ILD (RP-ILD) and amyopathic dermatomyositis (DM) than anti-aminoacyl-tRNA synthetase (ARS) antibodies and that serum ferritin levels are higher in anti-MDA5-positive patients and serve as a relevant biomarker for RP-ILD [1]. Thus, it is speculated that anti-MDA5 DM and anti-ARS idiopathic inflammatory myopathies (IIMs) have distinct pathomechanisms. It was reported that type I interferon (IFN) gene signature was upregulated in the peripheral blood mononuclear cells and the skin tissues from the anti-MDA5 DM patients [2]. However, the role of type I IFN in anti-MDA5 DM has yet to be fully elucidated. <h3>Objectives</h3> We aimed to determine the activity of IFN-α/β and IFN regulatory factor (IRF) in sera of patients with anti-MDA5 antibody-positive DM with ILD, compare them to those of patients with anti-ARS antibody-positive polymyositis (PM) and DM with ILD, and investigate their association with clinical features. <h3>Methods</h3> Serum samples were collected from clinically active adult patients with anti-MDA5 antibody-positive DM (MDA5, <i>n</i> = 22), and anti-ARS antibody-positive PM and DM (ARS, <i>n</i> = 21) as well as healthy controls (HCs, <i>n</i> = 32). PM/DM were classified according to the 2017 EULAR/ACR classification criteria for IIMs. Only patients with ILD diagnosed on high-resolution computed tomography findings and HCs were included. Patients complicated by infection or malignancy were excluded. The reporter cell lines (purchased from InvivoGen) which secrete embryonic alkaline phosphatase (SEAP) in response to IFN-α/β and those secrete luciferase and SEAP in response to activation of IRFs and nuclear factor kappa B (NF-κB), respectively, were incubated with 20% (v/v) serum samples. The levels of SEAP and luciferase in supernatants were measured using a multi-mode microplate reader and their association with clinical features was statistically analyzed. IFNAR2-knockout reporter cells were also used. <h3>Results</h3> The sera of MDA5 patients demonstrated significantly higher IFN-α/β and IRF activities than those of ARS patients and HCs (<i>p</i> &lt; 0.001 in all the comparisons), whereas no significant difference was detected in the NF-κB activities (Figure 1). The assays using IFNAR2-knockout reporter cells showed no significant difference in IRF or NF-κB activities. The serum ferritin levels in MDA5 patients were significantly higher than those in ARS patients (mean 679.7 ng/mL vs. 321.3 ng/mL, <i>p</i> = 0.03). The IFN-α/β and IRF activities induced by the MDA5 patients sera were correlated with the serum ferritin levels (<i>r</i> = 0.53 and 0.54, respectively), whereas they did not significantly correlate with the serum KL-6 levels, percent-predicted forced vital capacity (%FVC), or percent-predicted diffusing capacity of the lung for carbon monoxide (%DLCO). <h3>Conclusion</h3> IFN-α/β and IRF activities and their association with ferritin were demonstrated in sera of anti-MDA5-positive DM patients with ILD but not in those of anti-ARS-positive PM/DM patients with ILD. The present study suggests that activation of type I interferon pathway may be involved in the pathomechanisms of anti-MDA5 DM with ILD. <h3>References</h3> [1]<i>Rheumatology (Oxford</i>). 2010;49:1354. [2]<i>Front Med (Lausanne</i>). 2022;8:833114. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Shohei Nakamura: None declared, Yasuhiro Katsumata Speakers bureau: GlaxoSmithKline K.K., AstraZeneca K.K., Sanofi K.K., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Asahi Kasei Pharma, Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, Yuko Okamoto: None declared, Masayoshi Harigai: None declared